Project Summary Pulmonary hypertension (PH) is a devastating disease of the pulmonary vasculature characterized by high blood pressure in the pulmonary arteries. Current therapies to treat PH have significant limitations and substantial costs. Currently there are approved therapies serving less than 15% of patients with PH. In contrast to the intense therapeutic focus on local pulmonary vasoactive mediators, relatively limited attention has been directed towards the important role played by the autonomic nervous system in PH. Sympathetic over activity plays a critical role in PH and recent studies have highlighted the role of invasive sympathetic denervation in management of pulmonary hypertension. Recently, a novel approach to localize pulmonary vascular sympathetic blockade has emerged: pulmonary artery denervation (PADN), which blocks the sympathetic efferent component of the pulmonary reflex (vasoconstriction) by ablation of the nerves immediately adjacent to the pulmonary artery using an intravascular catheter equipped with ablation elements. Preliminary clinical trials of PADN have shown that it effective in reducing pulmonary pressures, leading to sustained improvement in six- minute walk test distance and tricuspid excursion. Key limitations to the currently available method of PADN include its invasive nature, potential for PA injury, and need for specialized equipment/expertise. Our proposal will prove the feasibility of a completely new, minimally invasive bronchoscopic method to reduce sympathetic signaling to the pulmonary vasculature for the treatment of PH. Our approach is a novel in that we are able to exploit the anatomy of the cardio-pulmonary nerves to achieve substantial bilateral sympathetic denervation and reduce pulmonary pressures at a single site in front of the tracheal bifurcation known as the cardio-pulmonary plexus. We can access this region using techniques known to interventional pulmonologists. This project will be completed in several sequential stages. For this Phase I SBIR we will demonstrate proof of physiological and technical concept in a well-established canine model of PH. In this model, we will demonstrate that block of the cardio-pulmonary plexus in the pretracheal region significantly reduces the response to electrical stimulation of bilateral stellate ganglia and is safe /effective at reducing pulmonary pressures. Successful completion of the specific aims will lead to development lead to development of a clinical-grade device to safely and effectively denervate the cardio-pulmonary plexus, planned for Phase II of the project. Sympathetic over activity is uniformly associated with poor survival in PH. This work will validate a new method for interrupting sympathetic signaling to the pulmonary plexus that we believe will ultimately become the first-line therapy for many patients suffering from PH.